The present invention relates to novel substituted pyrimidine derivatives which have an amide bond in the 5-position, processes for producing the derivatives, and pharmaceutical compositions containing the pyrimidine derivatives for the treatment and/or prevention of arteriosclerosis or hyperlipidemia.
In recent years, arteriosclerosis has been recognized as a rapidly increasing disease in circulatory disorder, and is also given much attention as a basal lesion for serious disease. Arteriosclerosis causes various ischemic diseases or bleeding, for example, the ischemic heart disease due to coronary atherosclerosis, such as angina pectoris and myocardial infarction the cerebrovascular disease due to cerebrovascular arteriosclerosis, such as cerebral infarction and cerebral apoplexy, the optic nerve atrophy and hydrocephalia due to compression by cerebral arteriosclerosis, nephrosclerosis due to kidney arteriosclerosis, and aneurysm and arteriosclerosis obliterans due to stenosis in the lumen of the aorta and peripheral artery. Such diseases and occasionally fatal. It is generally said that hypertension, hyperlipidemia, smoking, obesity, diabetes and the like contribute to arteriosclerosis, especially pultaceous atherosclerosis. It is also known that cholesterinosis, calcinosis and foam cells derived from macrophages or vascular smooth muscle cells appear in sclerosis lesions. However, a clear mechanism for arteriosclerosis has not been elucidated, hence sufficient treatment and/or prevention of arteriosclerosis have yet to be established. In order to treat these diseases, drugs which can decrease serum cholesterol has been developed. Colestyramine and melinamide, which are inhibitors of cholesterol absorption from the intestine, and clofibrate, which partially facilitates cholesterol metabolism, are typical examples. As the mechanism of transport of serum cholesterol is gradually understood, drugs which regulate the balance of serum cholesterol level have also been developed. However, these drugs have not been effective in the prevention or treatment of arteriosclerosis. The development of drugs which lower the serum cholesterol level by the inhibition of cholesterol biosynthesis (HMG-CoA reductase inhibitors, squalene epoxidase inhibitors) has also been progressed. On the other hand, drugs that are antagonistic to platelet derived growth factor (PDGF) which inhibit the proliferation of vascular smooth muscle cells, and drugs which prevent macrophage infiltration to the arterial wall and the formation of foam cell, are also given much attention as a remedy for arteriosclerosis. Especially, in the stud of arteriosclerosis lesions, macrophage which transform into foam cell after scavenging degenerated lipids has been recognized as an essential factor which links hyperlipidemia to arteriosclerosis. It has also been said that the acyl-CoA cholesterol acyltransferase (ACAT) plays an important role on the onset of arteriosclerosis. That is to say, ACAT facilitates dietary cholesterol absorption from the intestine by esterification of free cholesterol at the intestinal mucosa. Furthermore, it is indicated that ACAT contributes to the formation of deposit of cholesterol esters derived from the above macrophage in the arterial wall. Therefore, ACAT inhibitors have been expected to lowering the level of serum lipids, and have been used for the treatment and/or prevention of arteriosclerosis.
Until now, various kinds of drugs for the treatment of arteriosclerosis have been developed, and some compounds directed to ACAT inhibition are described in JP-A-60 41655 and JP-A-2 117651. However, the development of these compounds has been discontinued since some of the compounds did not exhibit significant efficacy in clinical studies, and others had adverse effects on the liver, despite the good effects in lowering serum cholesterol in the animal models.
Although JP-A-62 258366 and JP-A-3 120243 exhibit pyrimidineamide compounds as anti-arteriosclerotic agents with an inhibitory effect on ACAT, the structures of these compounds are distinguishable from those of the present invention, and only a portion of inhibitory activities on ACAT in a variety of animal cells in vitro is shown. Further, there is no disclosure about any toxicological study in connection with the compounds described in JP-A-62 25866 and JP-A-3 120243.
Under these circumstances, anti-arteriosclerotic agents which possess beneficial effects directly on the arterial wall with good clinical efficacy and high safety in Homo sapiens are desired.